The effect of intrathecal pethidine on post-spinal anesthesia shivering after cesarean section: a systematic review and meta-analysis

Background: Spinal anesthesia is the most preferred method for cesarean section (C-section). This meta-analysis was performed to determine the effect of low and high intrathecal doses of pethidine on the maternal outcomes after C-section. Methods: A systematic search of PubMed, Scopus, Cochrane Library, and Google Scholar was performed. Random-effects meta-analysis was performed to derive odds ratios (ORs) from dichotomous data. Results: Seventeen randomized controlled trials with 1304 C-section patients were included. Patients who had received intrathecal pethidine experienced decreased shivering and intensity of shivering (OR 0.13; P<0.001) and (OR 0.21; P<0.001), respectively. Moreover, vomiting (OR 2.47; P=0.002) and pruritus (OR 5.92; P<0.001) were significantly higher in the pethidine group. There was no statistically significant difference in the incidence of nausea (OR 2.55; P=0.06) and hypotension (OR 0.91; P=0.67). Conclusions: Intrathecal pethidine can effectively decrease shivering, although it increases the risk of vomiting and pruritus. No significant difference was found both in the maternal hypotension and nausea.


Introduction
Spinal anesthesia is the most used anesthesia for elective and emergency cesarean section (CS) scenarios due to its simplicity and effective performance, low cost and quick application of anesthesia, providing sufficient analgesia and muscle relaxation for the procedure [1,2] .It is suggested by the Royal College of Obstetricians and Gynecologists that CS should be performed "with an urgency appropriate to the risk to the baby and the safety of the mother" as the target decision to delivery interval is achieved [3] .Anesthetic goals during CS include a specific anesthetic level to optimize surgical conditions and reduce maternal recall; adequate oxygenation of the mother and fetus; and minimal transfer of anesthesia to fetus [4] .CS is likely to have several adverse effects on the mother and the baby.For instance, mothers experience pain post-C-section likely due to spinal anesthesia wearing off without additional analgesia given [5] .Additionally, mothers experience hypotension, which is the most common minor postoperative

HIGHLIGHTS
• Pethidine is a synthetic phenylpiperidine derivative opioid that acts on μ and κ opioid receptors.Intravenous (IV) pethidine has long been used to treat and prevent shivering during surgery and the emergence from anesthesia.The anti-shivering mechanism is activated by IV pethidine acting on kappa-opioid receptors.• Unlike IV pethidine, the advantages and disadvantages of intrathecal pethidine are unclear.• Intrathecal pethidine effectively reduces the severity and incidence of post-spinal anesthesia shivering.• Low doses increase pruritus, nausea, and vomiting while showing no association with hypotension.• Surgeons could consider administering intrathecal pethidine at appropriate doses to subside PSAS effectively.However, continuous monitoring is needed to manage the side effects.
complication of spinal anesthesia.Maternal hypotension is associated with bouts of nausea and vomiting with a risk of fetal acidosis.Shivering is another postoperative complication that can be troublesome as it interferes with the comfort and monitoring of the mother.Shivering results in increased oxygen consumption and carbon dioxide production, especially in mothers with low (thermoregulatory shivering) and high core temperatures (non-thermoregulatory shivering) [6,7] .Pethidine or Meperidine is a synthetic phenylpiperidine derivative opioid that acts on μ and k opioid receptors.For a long period of time, intravenous (IV) pethidine has been used for the treatment and prevention of shivering during surgery and emergence.The anti-shivering mechanism is activated by IV pethidine acting on kappa-opioid receptors.Unlike IV pethidine, advantages and disadvantages of intrathecal pethidine are unclear [8,9] .For this purpose, we conducted this systematic review and meta-analysis to determine the efficacy of low-dose and high-dose intrathecal pethidine on CS patients with spinal anesthesia.

Methods
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA, Supplemental Digital Content 1, http://links.lww.com/MS9/A563) [10]and the framework laid out by the Cochrane Collaboration [11] .

Literature search and study selection
A comprehensive literature search of electronic databases, PubMed, Scopus, and Cochrane Library was performed from inception till September 2023.The following keywords were used in the search string: "meperidine", "pethidine", "intrathecal", "spinal anesthesia", and "cesarean section".Detailed search strategy used in each database is shown in supplementary material Table S1, Supplemental Digital Content 2, http://links.lww.com/MS9/A564.
Articles initially shortlisted from each database were exported to Endnote Reference Library (Version X7.5; Clarivate Analytics, Philadelphia, Pennsylvania) software, where deduplication was performed.Two reviewers thoroughly reviewed the remaining articles first by title, then abstract, and finally a full-text evaluation was performed based on a preset eligibility criterion.Disagreements were resolved by consensus.The following inclusion criteria was employed to shortlist studies (1): randomized controlled trials (RCTs) (2), females undergoing cesarean section with spinal anesthesia (3), intrathecal meperidine (pethidine) administration between 5 and 50 mg (4), compared with bupivacaine or normal saline (5), studies involving the measurement of shivering or intensity of shivering.No language restrictions were placed when shortlisting articles.Exclusion criteria were the use of local anesthesia, non-elective surgery, combination of opioids in intervention or control, studies of observational nature, and studies whose full text was unavailable.

Data extraction and quality assessment
Two independent reviewers conducted the data extraction.Any disagreement was resolved by discussion.Additionally, a snowball searching method was applied where articles were found by going through the citations of relevant articles.Data extraction was performed of the following characteristics: study design, country of study, number of patients in each group, dosage of pethidine, and primary and secondary endpoints.In this study incidence and severity of shivering were the primary outcomes.Adverse events including pruritus, nausea, vomiting, and hypotension were the secondary outcomes.Quality assessment was performed using the Risk of Bias-2 (RoB-2) tool of the Cochrane Collaboration for randomized controlled trials [12] .Differences between the two independent reviewers in quality assessment were resolved by discussion.We performed an evaluation of our meta-analysis using the AMSTAR-2 checklist, Supplemental Digital Content 3, http://links.lww.com/MS9/A565 [13].Our meta-analysis was found to be of high-quality.

Results
A total of 737 articles were shortlisted from the literature search.
After removing duplicates and articles based on study design, patient population, and intervention, a total of 65 were given a full-text evaluation (Fig. 1).A total of 17 studies falling under our eligibility criteria were included in this systematic review and meta-analysis [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] .From these 17 studies, 13 had data on pethidine dose less than 20 mg and 11 included doses greater than 20 mg.This cut-off was used due to the greater and lesser effects of pethidine and approximately equal number of studies on both sides of the 20 mg mark.Seven hundred thirty-eight patients were included in the pethidine group and 566 in the control group.Study characteristics are shown in Table 1.Detailed characteristics of the included RCTs are shown in Table 2.

Quality assessment and publication bias
Quality assessment was performed using RoB-2 tool in which five domains are assessed for bias.All the included RCTs were found to be at a low risk of bias.Three studies showed some concerns in the randomization process whereas, two studies showed deviation from the intended interventions.Moreover, one study had a moderate risk of missing outcome data.Two articles had some concerns with the measurement of the outcome and three studies had some bias in the selection of results that were discussed.Detailed quality assessment is shown in supplementary figure S2, Supplemental Digital Content 5, http://links.lww.com/MS9/A567.Publication bias was assessed using funnel plot for the primary outcome shivering.Asymmetry was noted upon evaluating the funnel plot (Figure S3, Supplemental Digital Content 6, http://links.lww.com/MS9/A568).This was confirmed by Egger's regression test showing a two-tailed p-value of 0.0001.

Discussion
In this meta-analysis we evaluated the impact of low (< 20 mg) and high ( > 20 mg) dose of intrathecal pethidine on the incidence and severity of post-spinal shivering in women undergoing CS.Our study showed that intrathecal administration of pethidine in patients can significantly reduce post-spinal anesthesia shivering events.Additionally, pethidine was linked with lower severity of shivering.The intrathecal pethidine, however, increases the risk of pruritus and vomiting.No association was observed with nausea and hypotension events.
In the majority of the studies in our meta-analysis similar surgical procedures were followed when administering pethidine intrathecally.Firstly, patients received 5-7 ml/kg lactated Ringer's solution before spinal anesthesia.Then, a 25-gauge Quincke needle was inserted intrathecally via a midline approach between L3/L4 and L4/L5, while the patient was in a sitting position with 2-2.5 ml bupivacaine 0.5% with the prespecified dosage of pethidine.
A meta-analysis conducted by Lin et al. [31] studied the effect of low-dose intrathecal pethidine in patients undergoing various surgical procedures.They found significantly lower incidence and severity of post-spinal anesthesia shivering; however, nausea and vomiting were increased.Similar findings were observed by Subramani et al. [32] , who found intrathecal pethidine to lower severity and incidence of shivering in CS patients.The results of our meta-analysis are consistent with these findings.Recent randomized controlled trials by Girma et al. [19] and Azemati et al. [22] .show similar findings as shivering incidence was significantly reduced and severity of shivering was also found to be decreased in patients in the pethidine group.
Spinal anesthesia impedes tonic vasoconstriction and causes readjustment of core heat from the trunk to the periphery thereby patients develop hypothermia and shivering.Post-spinal anesthesia shivering is an involuntary, repetitive activity of skeletal muscles as a reaction to core hypothermia to raise metabolic heat production [9] .
Intravenous pethidine reduces the incidence of post-spinal anesthesia shivering by the reduction of shivering threshold and binding to the kappa receptors [9,33] .Possible mechanisms for intrathecal pethidine to reduce shivering could be k-opioid receptor activity, anticholinergic action, biogenic monoamine reuptake inhibition, NMDA receptor antagonism, or stimulation of alpha 2-adrenoceptors, and possibly modulating the heat loss caused by vasodilatation after spinal anesthesia [34][35][36] .
In a recent RCT by Azemati et al. [22] there was no significant association between intrathecal pethidine and nausea and vomiting.Similar findings were observed by Nasseri et al. [21] These results are contrary to what Lin et al. [31] found as low-dose intrathecal pethidine increased the incidence of nausea and vomiting.This is consistent with our meta-analysis as the lowdose (< 20 mg) subgroup showed increased nausea and vomiting events whereas the high dose ( > 20 mg) showed no significant association.Shami et al. [20] found 5, 10, 15 mg of intrathecal pethidine to be of no significance in causing vomiting and nausea.Since pethidine is an opiate, it inhibits the neurotransmission of pain by binding to the opioid receptors in the central nervous system [37] .Thus, pethidine could be attributed to nausea and vomiting caused by stimulation of the medullary chemoreceptor trigger zone [38] .
In our study, there was a significant association between both low-and high-dose intrathecal pethidine and pruritus.These findings are consistent with the study conducted by Jaafarpour et al. [39] .Recent RCT by Azemati et al. [22] found that concomitant use of pethidine and bupivacaine increased feeling of itching, which is also consistent with Bi et al. [40] as they compared the group that received hyperbaric bupivacaine with the groups treated by the pethidine in terms of side effects.They found that itching complications were more prevalent in the pethidine group.
Our meta-analysis is not without its limitations.Firstly, the included RCTs had a low sample size.Secondly, we decided on a low and high-dose cut-off of 20 mg on our own due to the equal statistical distribution of studies on either side and the low and high effects of pethidine observed on either side of the cut-off.Due to a low number of participants in some studies, it contributed to greater CIs in outcomes which resulted in increased heterogeneity.However, our meta-analysis has its strengths also.We included recent RCTs and conducted the meta-analysis with the greatest sample size as compared to previous meta-analysis on this topic.We found crucial dose-dependent associations that were not made previously.Since pethidine was statistically associated with decreasing severity and reduced post-spinal anesthesia shivering events, it could serve as a potent treatment in the clinical setting.However, caution is warranted with the dosing of pethidine as low dose (< 20 mg) was associated with increased adverse events.

Conclusion
Intrathecal pethidine is effective in reducing the severity and incidence of post-spinal anesthesia shivering.However, it increases pruritus, nausea, and vomiting in low doses and it had no association with hypotension.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart.

Figure 2 .
Figure 2. Forest plot of incidence of shivering.

Figure 3 .
Figure 3. Forest plot of intensity of shivering.

Figure 4 .
Figure 4. Forest plot of incidence of pruritus.

Figure 5 .
Figure 5. Forest plot of incidence of nausea.

Figure 6 .
Figure 6.Forest plot of incidence of vomiting.

Figure 7 .
Figure 7. Forest plot of incidence of hypotension.

Table 1
Characteristics of the included studies

Table 2
Detailed trial characteristics